TCF1highPD-1+Ly108+CD8+ T Cells Are Associated with Graft Preservation in Sensitized Mice Treated with Non-Fc Receptor-Binding CD3 Antibodies.

The non-Fc-binding anti-CD3 Ab [anti-CD3F(ab')2] can induce graft acceptance depending on the therapeutic window in a rodent heart transplant model. The delayed protocol allows for early graft infiltration of lymphocytes, which may behave in an inhibitory manner. We investigated the most effective protocol for anti-CD3F(ab')2 in sensitized conditions to confirm the evidence for clinical application. C57BL/6 mice were sensitized with BALB/c tail skin grafts and transplanted with BALB/c heart grafts at 8-12 wk after sensitization. Fifty micrograms of anti-CD3F(ab')2 was administered daily for 5 consecutive days on days 1-5 (day 1 protocol) or days 3-7 (delayed protocol). In nonsensitized mice, the delayed protocol significantly prolonged graft survival after transplantation from BALB/c to naive B6 (median survival time [MST], >100 d). In contrast, the delayed protocol was unable to prevent graft rejection in sensitized mice (MST, 5 d). A significantly increased percentage of granzyme B+ CD8+ T cells was observed in the graft on day 3 posttransplantation in sensitized conditions. Further, the day 1 protocol significantly prolonged graft survival (MST, 18 d), even in sensitized conditions. Day 1 treatment significantly increased the percentage of Foxp3+CD25+CD4+ T cells and phenotypically changed CD8+ T cells in the graft (i.e., caused a significant increase in the proportion of Ly108+TCF1highPD-1+CD8+ T cells). In conclusion, different timings of delayed anti-CD3F(ab')2 treatment promoted allograft preservation in association with phenotypic changes in CD4+ and CD8+ T cells in the graft under sensitized conditions.

Important Constituents of Heavy Water-containing Solution for Cold Storage and Subsequent Reperfusion on an Isolated Perfused Rat Liver.

The University of Wisconsin (UW) solution is the most effective preservation solution currently used; however, to safely use expanded-criteria donor grafts, a new cold storage solution that alleviates graft injury more effectively is required. We prepared a heavy water (D2O)-containing buffer, Dsol, and observed strong protective effects during extended cold storage of rat hearts and livers. In the current study, we modified Dsol (mDsol) and tested its efficacy. The aim of the present study was to determine whether mDsol could protect the rat liver more effectively than the UW solution and to clarify the roles of D2O and deferoxamine (DFX). Rat livers were subjected to cold storage for 48 hours in test solutions: UW, mDsol, mDsol without D2O or DFX (mDsol-D2O[-], mDsol-DFX[-]), and subsequently reperfused on an isolated perfused rat liver for 90 minutes at 37°C. In the UW group, the liver was dehydrated during cold storage and rapidly expanded during reperfusion. Accordingly, the cumulative weight change was the highest in the UW group, together with augmented portal veinous resistance and ALT leakage and decreased oxygen consumption rate and bile production. These changes were significantly suppressed in the mDsol-treated group. In the mDsol-D2O(-) and mDsol-DFX(-) groups offered partial protection. In conclusion, mDsol appeared to be superior to the UW solution for simple cold storage of the rat liver, presumably due to improved microcirculation in the early phase of reperfusion. Both heavy water and deferoxamine are essential for alleviating seamless organ swelling that occurs during cold storage and subsequent reperfusion.

Long-term risk of a fatty liver in liver donors.

Aim: Approximately 30 years have passed since the first experience of living donor liver transplantation. The time to evaluate the long-term safety of living donors has been fulfilled. Meanwhile, nonalcoholic fatty liver disease is increasingly common and a critical problem. The aim of this study was to evaluate the safety of living donor, focusing on fatty liver postdonation hepatectomy. Methods: Living donors (n = 212, 1997-2019) were evaluated by computed tomography (CT) at >1-year postdonation. A liver to spleen (L/S) ratio of <1.1 was defined as fatty liver. Results: Among 212 living liver donors, 30 (14.2%) detected fatty liver at 5.3 ± 4.2 years postdonation. The cumulative incidence rates of fatty liver were 3.1%, 12.1%, 22.1%, and 27.7% at 2, 5, 10, and 15 years postdonation, respectively. Of 30 subjects who developed fatty liver, 18 (60%) displayed a severe steatosis (L/S ratio <0.9). Five (16.7%) had a prior history of excessive alcohol abuse. More than 30% developed metabolic syndrome including obesity, hyperlipidemia, and diabetes. Although six (20%) had a Fib-4 index of >1.3, which included a case with a Fib-4 index of >2.67, no significant increased Fib-4 index was observed in the subjects with fatty liver as compared to those without fatty liver (p = 0.66). The independent predictive risk factors for developing fatty liver were male sex, pediatric recipient, and higher body mass index (>25) at donation. Conclusion: Living donors with risk factors for developing fatty liver should be carefully followed-up for the prevention and management of metabolic syndrome.

Post-transplant donor-specific anti-HLA antibodies with a higher mean fluorescence intensity are associated with graft fibrosis in pediatric living donor liver transplantation.

The roles of post-transplant anti-HLA donor specific antibody (DSA) in pediatric liver transplantation (LT), including therapeutic strategies, remain controversial. This study aimed to identify the risks of post-transplant DSA for graft fibrosis progression in pediatric living donor LT (LDLT). We retrospectively evaluated 88 LDLT pediatric cases between December 1995 and November 2019. DSAs were assessed with single antigen bead test. Graft fibrosis was histopathologically scored with METAVIR and the centrilobular sinusoidal fibrosis system. Post-transplant DSAs were detected in 37 (52.9%) cases at 10.8 (1.3-26.9) years post-LDLT. The histopathological examination of 32 pediatric cases with post-transplant DSA revealed that 7 (21.9%) with a high DSA-MFI (≥9,378) showed graft fibrosis progression (≥F2). No graft fibrosis was observed in the subjects with a low DSA-MFI. The risk factors for developing graft fibrosis in pediatric cases with post-transplant DSA were an older graft age (>46.5 years old), lower platelet count (<10.7 × 104/ml) and higher Fib4 index (>0.7807, recipient age; >1.8952, donor age). Limited efficacy of additional immunosuppressants was observed in DSA positive pediatric cases. In conclusion, pediatric cases with a high DSA-MFI and risk factors should undergo a histological examination. The appropriate treatment for post-transplant DSA in pediatric LT needs to be determined.

Warm Ischemia Induces Spatiotemporal Changes in Lysophosphatidylinositol That Affect Post-Reperfusion Injury in Normal and Steatotic Rat Livers.

Warm ischemia-reperfusion injury is a prognostic factor for hepatectomy and liver transplantation. However, its underlying molecular mechanisms are unknown. This study aimed to elucidate these mechanisms and identify the predictive markers of post-reperfusion injury. Rats with normal livers were subjected to 70% hepatic warm ischemia for 15, 30, or 90 min, while those with steatotic livers were subjected to 70% hepatic warm ischemia for only 30 min. The liver and blood were sampled at the end of ischemia and 1, 6, and 24 h after reperfusion. The serum alanine aminotransferase (ALT) activity, Suzuki injury scores, and lipid peroxidation (LPO) products were evaluated. The ALT activity and Suzuki scores increased with ischemic duration and peaked at 1 and 6 h after reperfusion, respectively. Steatotic livers subjected to 30 min ischemia and normal livers subjected to 90 min ischemia showed comparable injury. A similar trend was observed for LPO products. Imaging mass spectrometry of normal livers revealed an increase in lysophosphatidylinositol (LPI (18:0)) and a concomitant decrease in phosphatidylinositol (PI (18:0/20:4)) in Zone 1 (central venous region) with increasing ischemic duration; they returned to their basal values after reperfusion. Similar changes were observed in steatotic livers. Hepatic warm ischemia time-dependent acceleration of PI (18:0/20:4) to LPI (18:0) conversion occurs initially in Zone 1 and is more pronounced in fatty livers. Thus, the LPI (18:0)/PI (18:0/20:4) ratio is a potential predictor of post-reperfusion injury.

Combination of Cold Storage in a Heavy Water-Containing Solution and Post-Reperfusion Hydrogen Gas Treatment Reduces Ischemia-Reperfusion Injury in Rat Livers.

We previously reported the efficacy of cold storage (CS) using a heavy water-containing solution (Dsol) and post-reperfusion hydrogen gas treatment separately. This study aimed to clarify the combined effects of these treatments. Rat livers were subjected to 48-hour CS and a subsequent 90-minute reperfusion in an isolated perfused rat liver system. The experimental groups were the immediately reperfused control group (CT), the CS with University of Wisconsin solution (UW) group, the CS with Dsol group, the CS with UW and post-reperfusion H2 treatment group (UW-H2), and the CS with Dsol and post-reperfusion H2 group (Dsol-H2). We first compared the Dsol-H2, UW, and CT groups to evaluate this alternative method to conventional CS. The protective potential of the Dsol-H2 group was superior to that of the UW group, as evidenced by lower portal venous resistance and lactate dehydrogenase leakage, a higher oxygen consumption rate, and increased bile production. Multiple comparison tests among the UW, Dsol, UW-H2, and Dsol-H2 groups revealed that both treatments, during CS and after reperfusion, conferred a similar extent of protection and showed additive effects in combination therapy. Furthermore, the variance in all treatment groups appeared smaller than that in the no-treatment or no-stress groups, with excellent reproducibility. In conclusion, combination therapy with Dsol during CS and hydrogen gas after reperfusion additively protects against graft injury.

Rapid and Reliable Steatosis Rat Model Shrsp5-Dmcr for Cold Storage Experiment.

Interventions for liver grafts with moderate macrovesicular steatosis have been important in enlarging donor pools. Here, we tested a high-fat and cholesterol (HFC) diet to create a steatosis model for cold hepatic preservation and reperfusion experiments. The aim of the present study was to assess the steatosis model's reliability and to show the resulting graft's quality for cold preservation and reperfusion experiment. Male SHRSP5-Dmcr rats were raised with an HFC diet for up to 2 weeks. The fat content was evaluated using magnetic resonance imaging (MRI) proton density fat fraction (PDFF). The nonalcoholic fatty liver disease activity score (NAS) was evaluated after excision. Steatosis created by 2 weeks of HFC diet was subjected to 24-hour cold storage in the University of Wisconsin and the original test solution (new sol.). Grafts were applied to isolated perfused rat livers for simulating reperfusion. The NAS were 2.2 (HFC 5 days), 3.3 (HFC 1 week), and 5.0 (HFC 2 weeks). Ballooning and fibrosis were not observed in any group. An MRI-PDFF showed 0.2 (HFC 0 days), 12.0 (HFC 1 week), and 18.9 (HFC 2 weeks). The NAS and MRI-PDFF values correlated. Many indices in the isolated perfused rat liver experiment tended to improve in the new sol. group but were insufficient. Although the new sol. failed to be effective, it acted at multiple sites under difficult conditions. In conclusion, the HFC diet for 2 weeks in SHRSP5-Dmcr rats, together with MRI-PDFF evaluation, is a reliable method for creating simple steatosis and provides good-quality cold preservation and reperfusion experiments.

Hypothermic Machine Perfusion with Hydrogen Gas Reduces Focal Injury in Rat Livers but Fails to Restore Organ Function.

BACKGROUND: We have previously reported the efficacy of post-reperfusion H2 gas treatment in cold storage (CS) and subsequent reperfusion of the rat liver. The present study aimed to evaluate the effect of H2 gas treatment during hypothermic machine perfusion (HMP) in rat livers retrieved from donation after circulatory death (DCD) and elucidate the mechanism of action of H2 gas. METHODS: Liver grafts were procured from rats after 30 min of cardiopulmonary arrest. The graft was subjected to HMP for 3 hours at 7°C using Belzer MPS with or without dissolved H2 gas. The graft was reperfused using an isolated perfused rat liver apparatus at 37°C for 90 minutes. Perfusion kinetics, liver damage, function, apoptosis, and ultrastructure were evaluated. RESULTS: Portal venous resistance, bile production, and oxygen consumption rates were identical in the CS, MP, and MP-H2 groups. Liver enzyme leakage was suppressed by MP (vs control), whereas H2 treatment did not show a combination effect. Histopathology revealed poorly stained areas with a structural deformity just below the liver surface in the CS and MP groups, whereas these findings disappeared in the MP-H2 group. The apoptotic index in the CS and MP groups was high but decreased in the MP-H2 group. Mitochondrial cristae were damaged in the CS group but preserved in the MP and MP-H2 groups. CONCLUSIONS: In conclusion, HMP and H2 gas treatment are partly effective in DCD rat livers but insufficient. Hypothermic machine perfusion can improve focal microcirculation and preserve mitochondrial ultrastructure.

[Successful treatment of a fulminant-type Wilson's disease with deceased donor liver transplantation after recovery from critical illness].

A 15-year-old female patient was diagnosed with a fulminant-type Wilson's disease. She had severe illness with a Model for End-Stage Liver Disease score of 25 and new Wilson Index score of 11. She underwent plasma exchanges, hemodiafiltration, and administration of fresh frozen plasma on consecutive days. Finally, she had recovered from severe illness and was discharged from the hospital. After 18 months of waiting time, she underwent deceased liver transplantation and returned to normal daily life. In Japan, the critical shortage of donated organs requires a long waiting time. Previous studies demonstrated that artificial liver support systems, including plasma exchange and hemodiafiltration, could be useful for a fulminant-type Wilson's disease. For such a disease, multidisciplinary bridging treatments are crucial for a successful liver transplantation.

Prediction of the need for emergency endoscopic treatment for upper gastrointestinal bleeding and new score model: a retrospective study.

BACKGROUND: Gastrointestinal bleeding is one of the major gastrointestinal diseases. In this study, our objective was to compare Glasgow-Blatchford score (GBS), AIMS65 score, MAP score, Modified GBS, and Iino score as outcome measures for upper gastrointestinal bleeding. In addition, we extracted factors associated with hemostatic procedures including endoscopy, and proposed a new robust score model. METHODS: From January 2015 to December 2019, 675 patients with symptoms such as hematemesis who visited the National Hospital Organization Disaster Medical Center and underwent urgent upper endoscopy with diagnosis of suspected non-variceal upper gastrointestinal bleeding were retrospectively reviewed. We evaluated the GBS, AIMS65 score, MAP score, Modified GBS, and Iino score, and assessed the outcomes of patients requiring hemostatic treatments at the subsequent emergency endoscopy. We performed logistic regression analysis of factors related to endoscopic hemostasis and upper gastrointestinal bleeding, created a new score model, and evaluated the prediction of hemostatic treatment and mortality in the new score and the existing scores. RESULTS: The factors associated with endoscopic treatment were hematemesis, heart rate, HB (hemoglobin), blood pressure, blood urea nitrogen (BUN). Based on these predictors and the partial regression coefficients, a new score named H3B2 (using the initial letters of hematemesis, heart rate, HB, blood pressure, and BUN) was generated. H3B2 score was slightly more discriminatory compared to GBS and Modified GBS (area under the receiver operating characteristic curves (AUROC): 0.73 versus 0.721 and 0.7128, respectively) in predicting hemostatic treatment in emergency endoscopy. The H3B2 score also showed satisfactory prediction accuracy for subsequent deaths (AUROC: 0.6857. P < 0.001). CONCLUSIONS: We proposed a new score, the H3B2 score, consisting of simple and objective indices in cases of suspected upper gastrointestinal bleeding. The H3B2 score is useful in identifying high-risk patients with suspected upper gastrointestinal bleeding who require urgent hemostatic treatment including emergency endoscopy.

Living Donor Liver Transplantation for Hepatic Venoocclusive Disease/Sinusoidal Obstruction Syndrome Originating from Hematopoietic Stem Cell Transplantation.

Background: Venoocclusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a life-threatening hematopoietic stem cell transplantation (HSCT) complication. Cases of mild and moderate VOD/SOS are self-limiting; however, the mortality for severe VOD/SOS has reached 80%. Recently, defibrotide became available and has been used for VOD/SOS; however, the outcome for patients with severe VOD/SOS is not satisfactory, and liver transplantation is attempted in these severe cases. Method: We describe a case of living donor liver transplantation (LDLT) for acute liver failure secondary to VOD/SOS that originates from HSCT. Result: Liver regeneration after LDLT was impaired, and several infections were developed before liver regeneration completion. Our patient suffered sepsis and finally died of multiorgan failure. Conclusion: Severe VOD/SOS originating from HSCT is associated with a very poor prognosis. The liver transplantation outcome for VOD/SOS has not been satisfied, but it may provide long-term survival if successful. We considered liver transplantation as a therapeutic option, especially in cases where sufficient graft volume is secured, considering impaired liver regeneration under bone marrow suppression after HSCT.

Efficient multiple treatments including molecular targeting agents in a case of recurrent hepatocellular carcinoma, post-living donor liver transplantation.

Despite the promising efficacies of recently developed molecular targeting therapies for hepatocellular carcinoma, their role in liver transplantation is unknown. Here we report that multidisciplinary treatment, including novel molecular targeting therapy with lenvatinib, achieved long-term survival of a patient with post-liver transplantation recurrence of hepatocellular carcinoma. A 62 year-old man with hepatocellular carcinoma beyond the Milan criteria, arising from hepatitis B virus-associated cirrhotic liver, underwent living donor liver transplantation. However, alpha-fetoprotein level increased a month post-transplantation, and pleural dissemination and lung metastasis of hepatocellular carcinoma in the right lung were detected. The patient was initially treated with sorafenib and rapamycin, right pleurectomy and upper and middle lobectomies were attempted as the second treatment. However, remnant tumors started to grow. Subsequently, the newly molecular targeting agents; regorafenib and lenvatinib, approved for recurrent hepatocellular carcinoma in Japan, were administered. Lenvatinib efficiently reduced tumor volumes and the alpha-fetoprotein level, which contributed to maintaining better quality of life for 26 months as an outpatient. Unfortunately, sepsis caused by cholangitis and liver abscess required the discontinuation of lenvatinib, and the patient died 73 months after the recurrence of hepatocellular carcinoma. Multidisciplinary treatment including lenvatinib is potentially acceptable for recurrent hepatocellular carcinoma after liver transplantation.

Liver Transplantation for Hepatocellular Carcinoma: How Should We Improve the Thresholds?

Hepatocellular carcinoma (HCC) is the third highest cause of cancer-related mortality, and liver transplantation is the ideal treatment for this disease. The Milan criteria provided the opportunity for HCC patients to undergo LT with favorable outcomes and have been the international gold standard and benchmark. With the accumulation of data, however, the Milan criteria are not regarded as too restrictive. After the implementation of the Milan criteria, many extended criteria have been proposed, which increases the limitations regarding the morphological tumor burden, and incorporates the tumor's biological behavior using surrogate markers. The paradigm for the patient selection for LT appears to be shifting from morphologic criteria to a combination of biologic, histologic, and morphologic criteria, and to the establishment of a model for predicting post-transplant recurrence and outcomes. This review article aims to characterize the various patient selection criteria for LT, with reference to several surrogate markers for the biological behavior of HCC (e.g., AFP, PIVKA-II, NLR, 18F-FDG PET/CT, liquid biopsy), and the response to locoregional therapy. Furthermore, the allocation rules in each country and the present evidence on the role of down-staging large tumors are addressed.

The impact of preformed donor-specific antibodies in living donor liver transplantation according to graft volume.

INTRODUCTION: The roles of preformed anti-HLA donor-specific antibodies (DSAs) in liver transplantation remain controversial. We evaluated the impact of preformed DSAs in living donor liver transplantation. METHODS: Adults who underwent living donor liver transplantation (n = 175) in our institute were included in this study. Lymphocyte cytotoxicity test (LCT), flow cytometric crossmatch (FCXM), and single-antigen bead assays were performed. RESULTS: Among adult living donor liver transplantation recipients, 27 (16.5%) and 14 (8.5%) had pretransplant FCXM-positive findings and LCT-positive findings, respectively. FCXM-positive patients displayed a significantly worse 5-year graft survival rate (77.3%; vs. DSA-negative, 91.6%). Six of 14 LCT-positive patients exhibited graft loss shortly after transplantation (5-year survival rate: 57.1%). All LCT-positive patients with graft loss underwent left lobe living donor liver transplantation. Significantly lower ratio of graft volume relative to standard liver volume (32.9 ± 5.7%) and smaller graft size (365.3 ± 57.9 g) were observed in patients with graft loss (p < .03, vs. surviving grafts). Significantly higher DSA-mean fluorescence intensity (MFI) values were present in patients with graft loss (p = .0012, vs. surviving grafts). CONCLUSIONS: Patients with preformed DSAs exhibited worse graft outcomes in living donor liver transplantation. Higher DSA-MFI values and smaller graft size were associated with worse outcomes in LCT-positive patients. High-risk patients with preformed DSAs should be considered for appropriate graft selection and application of a desensitization protocol.

Functional roles of graft-infiltrating lymphocytes during early-phase post-transplantation in mouse cardiac transplantation models.

Immunological behavior of graft-infiltrating lymphocytes (GILs) determines the graft fate (i.e., rejection or acceptance). Nevertheless, the functional alloreactivity and the phenotype of GILs at various times during the early post-transplantation phase have not been fully elucidated. We examined the immunological activities of early-phase GILs using a murine model of cardiac transplantation. GILs from 120-h allografts, but not 72-h allografts, showed robust activation and produced proinflammatory cytokines. In particular, a significant increase in CD69+ T-bet+ Nur77+ T cells was detected in 120-h allografts. Furthermore, isolated GILs were used to reconstitute BALB/c Rag2-/- γc-/- (BRG) mice. BRG mice reconstituted with 120-h GILs displayed donor-specific immune reactivity and rejected donor strain cardiac allografts; conversely, 72-h GILs exhibited weak anti-donor reactivity and did not reject allografts. These findings were confirmed by re-transplantation of cardiac allografts into BRG mice at 72-h post-transplantation. Re-transplanted allografts continued to function for >100 days, despite the presence of CD3+ GILs. In conclusion, the immunological behavior of GILs considerably differs over time during the early post-transplantation phase. A better understanding of the functional role of early-phase GILs may clarify the fate determination process in the graft-site microenvironment.

A case report of percutaneous direct injection of N-butyl-2-cyanoacrylate (NBCA) to treat a pancreatic duodenal stump leak after a simultaneous pancreas and kidney transplantation.

BACKGROUND: Simultaneous pancreas and kidney transplantation (SPK) is a treatment option for patients with end-stage renal disease due to type 1 diabetes mellitus. We report a patient with a refractory fistula due to leakage from the duodenal stump of the pancreas graft after an SPK with bladder drainage who was successfully treated with a percutaneous direct injection of N-butyl-2-cyanoacrylate (NBCA). CASE PRESENTATION: A 60-year-old female with a 33-year history of type 1 diabetes mellitus and a 10-year history of renal replacement therapy underwent an SPK in 2015. At the time of transplantation, an abdominal aortic aneurysm with a high risk of rupture was treated by a Y-graft replacement prior to the SPK. Bladder drainage of the pancreas graft was chosen to avoid a vessel graft infection. The patient's postoperative course was uneventful. The patient was discharged on postoperative day 93 with good-functioning pancreas and kidney grafts. One and a half years after the operation, the patient was found to have acute graft pancreatitis and a leak from the duodenal stump of the pancreas graft due to a paralytic neurogenic bladder. The insertion of an indwelling catheter into the bladder and the endoscopic-guided insertion of a catheter into the graft pancreatic duct through the duodenum/bladder anastomosis did not result in the closure of the fistula. Therefore, NBCA was injected at the site of the leak point using CT-guided technique. The fistula was completely closed immediately after the injection, with no recurrences of leaks. CONCLUSIONS: A percutaneous direct injection of NBCA is one of the treatment options to treat intractable fistulas.

[A case of granulomatosis with polyangiitis with Crohn's disease-like findings].

A 22-year-old woman who was diagnosed with Crohn's disease experienced diarrhea and bloody stool. She was suspected of have aggravated Crohn's disease and was transferred to our hospital. Upper gastrointestinal endoscopy revealed multiple esophageal ulcers and erosive gastritis, while colonoscopy revealed multiple ulcers in the rectum to the sigmoid colon. Initially, the evidence suggested that the Crohn's disease had worsened, and consequently, prednisolone (PSL) therapy was initiated. However, the patient's condition was determined to be atypical inflammatory bowel disease, which was indicated by endoscopic findings and skin symptoms and because various test results did not meet the diagnostic criteria for Crohn's disease. As a result, her diagnosis was changed to granulomatosis with polyangiitis. Here, we report a case of granulomatosis with polyangiitis with gastrointestinal symptoms similar to Crohn's disease, both of which have been suggested to involve Th1/Th17 cells.

Imaging Mass Spectrometry Reveals the Changes in the Taurine Conjugates of Dihydroxycholanoic Acid During Hepatic Warm Ischemia and Reperfusion in a Rat Model.

Warm ischemia and reperfusion injury (IRI) is a prognostic factor in donation after cardiac death donor transplantation. However, a reliable method to predict IRI before transplantation has not been established. The aim of this study was to identify predictive markers of hepatic IRI by simultaneous measurement of endogenous molecules using matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS). Rats were subjected to hepatic warm ischemia (70%) for 30 or 90 minutes and subsequent reperfusion. The livers were collected at the end of ischemia and 1 hour, 6 hours, and 24 hours after reperfusion. The liver tissue sections were applied to IMS (m/z 200-2000). Candidate molecules were identified by tandem mass spectrometry. Imaging mass spectrometry (IMS) revealed a significant increase in the taurine conjugates of dihydroxycholanoic acid (TDHCA) during ischemia and a tendency to return to the basal level after reperfusion. Notably, high-resolution measurements revealed focal accumulation of TDHCA in the intrahepatic bile duct with ischemic time. In conclusion, IMS is a useful method to detect minute changes provoked by ischemia, which are barely detectable in assays involving homogenization. Accordingly, focal accumulation of TDHCA during ischemia may be a candidate marker for predicting later IRI.

Post-transplant indolent T cell lymphoproliferative disorder in living donor liver transplantation: a case report.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) of T cell type has been rarely reported. Accurate diagnosis of this life-threatening rare form of PTLD is important for the treatment strategy. CASE PRESENTATION: A 7-year-old boy had severe diarrhea and weight loss progressively at 7 years post-living donor liver transplantation (LDLT) for biliary atresia. Endoscopy in the gastrointestinal (GI) tract revealed multiple erosions and ulcer lesions with prominent intraepithelial lymphocytosis in the duodenum and terminal ileum. Immunohistochemical examination demonstrated that these accumulated lymphocytes mainly comprised small- to medium-sized T cells expressing CD3, CD4, CD5, CD7, and CD103, but lacking CD8, CD56, and Epstein-Barr virus-encoded small RNAs. In addition, T cell receptor ß gene rearrangement was detected by polymerase chain reaction analysis. Comprehensively, the lesions were best interpreted as post-transplant indolent T cell lymphoproliferative disorder (LPD) of the intestine. Clinical remission was achieved by reducing the immunosuppressant. CONCLUSION: A rarely reported indolent type of T cell LPD in post-LDLT was diagnosed by direct inspection and histological investigation. Although the histological classification and therapeutic strategy for post-transplant indolent T cell LPD have not been established, reducing immunosuppression allowed complete remission in our case. To prevent the incidence of PTLD and de novo malignancy, developing a methodology to set a proper dose of immunosuppressant is required.

Second Case of Deceased Donor Liver Transplantation in a Patient Co-infected with HIV and HCV in Japan: Special Reference to the Management of Complicated Coagulopathy Due to a Diverse Spectrum of Preformed Anti-HLA Antibodies.

We report the second case of deceased donor liver transplantation in a patient co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) in Japan. A 48-year-old patient with hemophilia A was infected with HIV and HCV through contaminated factor VIII concentrate in his childhood and developed cirrhosis and hepatocellular carcinoma. The patient was on the transplant list for a deceased donor liver. The patient had broad spectrum anti-HLA class I and II antibodies, which may be attributed to repeated whole blood transfusions in the past. Catastrophic coagulopathy during the surgery was predicted because of the underlying hemophilic status and severe thrombocytopenia requiring HLA-matched platelet products, which are difficult to obtain quickly. To maintain adequate platelet counts (> 5 × 104/µL) while awaiting liver transplantation, a thrombopoietin receptor agonist and rituximab were administered. During surgery, factor VIII concentrate was administered according to a previously planned protocol. Adequate hemostasis was obtained, and the operation was completed without uncontrollable coagulopathy. The postoperative course was uneventful, and the patient was discharged on postoperative day 41. Detailed planning is required for surgical patients with hemophilia and HIV/HCV cirrhosis, especially for those with a diverse spectrum of anti-HLA antibodies.